Modulation of osteoclast differentiation

Abstract

The present invention concerns the use of an aquaprin-9 (AQP-9) modulator for the preparation of a pharmaceutical composition for treating or preventing a pathological condition associated with unbalanced osteoclast differentiation. In accordance with one embodiment, the modulator is an AQP-9 inhibitor. An example of AQP-9 inhibitor is phloretin which has been shown to inhibit osteoclast differentiation, following induction of bone marrow cells with RANKL. The invention also concerns methods for modulating osteoclast differentiation, methods for prevention and treating pathological conditions associated with unbalanced osteoclast differentiation as well as pharmaceutical composition comprising such modulators.

The invention claimed is: 
     
       1. A method of modulating unbalanced osteoclast differentiation, in the treatment of osteoporosis, periodontal disease, aseptic loosening of prosthetic implants, or a bone disease manifested by excess bone loss, the method comprising:
 administering a therapeutically effective amount of phloretin to a subject in need thereof wherein the therapeutically effective amount inhibits aquaporin-9 (AQP-9) activity in one or more of osteoclast cells and osteoclast precursor cells. 
 
     
     
       2. The method according to  claim 1 , wherein said osteoclast precursor cells are mononuclear osteoclast cells. 
     
     
       3. The method according to  claim 1 , wherein the inhibition of the AQP-9 activity is demonstrated by at least one of the following:
 (a) reduction in size of osteoclasts; 
 (b) reduction in number of osteoclasts; and 
 (c) reduction in number of nuclei in an osteoclast. 
 
     
     
       4. The method according to  claim 1 , wherein the phloretin is administered by injecting directly to the subject's bone marrow. 
     
     
       5. The method according to  claim 1 , wherein the phloretin is administered by injecting into the subject's blood stream. 
     
     
       6. The method according to  claim 1 , wherein the phloretin is orally administered. 
     
     
       7. A method for treating osteoporosis, periodontal disease, or aseptic loosening of prosthetic implants, in a subject, comprising:
 administering a therapeutically effective amount of a pharmaceutical composition comprising phloretin and a pharmaceutically acceptable carrier to the subject in need thereof, wherein the therapeutically effective amount inhibits AQP-9 activity in one or more of osteoclast cells and osteoclast precursor cells. 
 
     
     
       8. The method according to  claim 7 , wherein the pharmaceutical composition is administered by injecting directly to the subject's bone marrow. 
     
     
       9. The method according to  claim 7 , wherein the pharmaceutical composition is administered by injecting into the subject's blood stream. 
     
     
       10. The method according to  claim 7 , wherein the pharmaceutical composition is orally administered.